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The Journal of Clinical Investigation Jan 20212021 to 2022 marks the one hundredth anniversary of ground-breaking research in Toronto that changed the course of what was, then, a universally fatal disease: type 1... (Review)
Review
2021 to 2022 marks the one hundredth anniversary of ground-breaking research in Toronto that changed the course of what was, then, a universally fatal disease: type 1 diabetes. Some would argue that insulin's discovery by Banting, Best, Macleod, and Collip was the greatest scientific advance of the 20th century, being one of the first instances in which modern medical science was able to provide lifesaving therapy. As with all scientific discoveries, the work in Toronto built upon important advances of many researchers over the preceding decades. Furthermore, the Toronto work ushered in a century of discovery of the purification, isolation, structural characterization, and genetic sequencing of insulin, all of which influenced ongoing improvements in therapeutic insulin formulations. Here we discuss the body of knowledge prior to 1921 localizing insulin to the pancreas and establishing insulin's role in glucoregulation, and provide our views as to why researchers in Toronto ultimately achieved the purification of pancreatic extracts as a therapy. We discuss the pharmaceutical industry's role in the early days of insulin production and distribution and provide insights into why the discoverers chose not to profit financially from the discovery. This fascinating story of bench-to-beside discovery provides useful considerations for scientists now and in the future.
Topics: Animals; Drug Industry; History, 20th Century; History, 21st Century; Humans; Insulin; Pancreas
PubMed: 33393501
DOI: 10.1172/JCI142239 -
Diabetes Technology & Therapeutics Dec 2020Insulin therapy has advanced remarkably over the past few decades. Ultra-rapid-acting and ultra-long-acting insulin analogs are now commercially available. Many... (Review)
Review
Insulin therapy has advanced remarkably over the past few decades. Ultra-rapid-acting and ultra-long-acting insulin analogs are now commercially available. Many additional insulin formulations are in development. This review outlines recent advances in insulin therapy and novel therapies in development.
Topics: Humans; Hypoglycemic Agents; Insulin; Insulin, Long-Acting; Insulin, Regular, Human
PubMed: 32310681
DOI: 10.1089/dia.2020.0065 -
Nature Metabolism Feb 2022Type 1 diabetes (T1D) is an autoimmune disease in which immune cells destroy insulin-producing beta cells. The aetiology of this complex disease is dependent on the...
Type 1 diabetes (T1D) is an autoimmune disease in which immune cells destroy insulin-producing beta cells. The aetiology of this complex disease is dependent on the interplay of multiple heterogeneous cell types in the pancreatic environment. Here, we provide a single-cell atlas of pancreatic islets of 24 T1D, autoantibody-positive and nondiabetic organ donors across multiple quantitative modalities including ~80,000 cells using single-cell transcriptomics, ~7,000,000 cells using cytometry by time of flight and ~1,000,000 cells using in situ imaging mass cytometry. We develop an advanced integrative analytical strategy to assess pancreatic islets and identify canonical cell types. We show that a subset of exocrine ductal cells acquires a signature of tolerogenic dendritic cells in an apparent attempt at immune suppression in T1D donors. Our multimodal analyses delineate cell types and processes that may contribute to T1D immunopathogenesis and provide an integrative procedure for exploration and discovery of human pancreatic function.
Topics: Diabetes Mellitus, Type 1; Humans; Insulin-Secreting Cells; Islets of Langerhans; Pancreas; Pancreatic Hormones
PubMed: 35228745
DOI: 10.1038/s42255-022-00531-x -
Nature Cancer Aug 2022Cancer-associated fibroblasts (CAFs) are one of the most prominent and active components in the pancreatic tumor microenvironment. Our data show that CAFs are critical...
Cancer-associated fibroblasts (CAFs) are one of the most prominent and active components in the pancreatic tumor microenvironment. Our data show that CAFs are critical for survival from pancreatic ductal adenocarcinoma (PDAC) on glutamine deprivation. Specifically, we uncovered a role for nucleosides, which are secreted by CAFs through autophagy in a nuclear fragile X mental retardation-interacting protein 1 (NUFIP1)-dependent manner, increased glucose utilization and promoted growth of PDAC. Moreover, we demonstrate that CAF-derived nucleosides induced glucose consumption under glutamine-deprived conditions and displayed a dependence on MYC. Using an orthotopic mouse model of PDAC, we found that inhibiting nucleoside secretion by targeting NUFIP1 in the stroma reduced tumor weight. This finding highlights a previously unappreciated metabolic network within pancreatic tumors in which diverse nutrients are used to promote growth in an austere tumor microenvironment.
Topics: Animals; Autophagy; Cancer-Associated Fibroblasts; Carcinoma, Pancreatic Ductal; Cell Proliferation; Glucose; Glutamine; Mice; Nuclear Proteins; Nucleosides; Pancreatic Hormones; Pancreatic Neoplasms; RNA-Binding Proteins; Tumor Microenvironment
PubMed: 35982178
DOI: 10.1038/s43018-022-00426-6 -
BMJ Open Diabetes Research & Care Aug 2021Insulin icodec is a novel, long-acting insulin analog designed to cover basal insulin requirements with once-weekly subcutaneous administration. Here we describe the... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
Insulin icodec is a novel, long-acting insulin analog designed to cover basal insulin requirements with once-weekly subcutaneous administration. Here we describe the molecular engineering and the biological and pharmacological properties of insulin icodec.
RESEARCH DESIGN AND METHODS
A number of in vitro assays measuring receptor binding, intracellular signaling as well as cellular metabolic and mitogenic responses were used to characterize the biological properties of insulin icodec. To evaluate the pharmacological properties of insulin icodec in individuals with type 2 diabetes, a randomized, double-blind, double-dummy, active-controlled, multiple-dose, dose escalation trial was conducted.
RESULTS
The long half-life of insulin icodec was achieved by introducing modifications to the insulin molecule aiming to obtain a safe, albumin-bound circulating depot of insulin icodec, providing protracted insulin action and clearance. Addition of a C20 fatty diacid-containing side chain imparts strong, reversible albumin binding, while three amino acid substitutions (A14E, B16H and B25H) provide molecular stability and contribute to attenuating insulin receptor (IR) binding and clearance, further prolonging the half-life. In vitro cell-based studies showed that insulin icodec activates the same dose-dependent IR-mediated signaling and metabolic responses as native human insulin (HI). The affinity of insulin icodec for the insulin-like growth factor-1 receptor was proportionately lower than its binding to the IR, and the in vitro mitogenic effect of insulin icodec in various human cells was low relative to HI. The clinical pharmacology trial in people with type 2 diabetes showed that insulin icodec was well tolerated and has pharmacokinetic/pharmacodynamic properties that are suited for once-weekly dosing, with a mean half-life of 196 hours and close to even distribution of glucose-lowering effect over the entire dosing interval of 1 week.
CONCLUSIONS
The molecular modifications introduced into insulin icodec provide a novel basal insulin with biological and pharmacokinetic/pharmacodynamic properties suitable for once-weekly dosing.
TRIAL REGISTRATION NUMBER
NCT02964104.
Topics: Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Insulin; Insulin, Long-Acting; Insulin, Regular, Human
PubMed: 34413118
DOI: 10.1136/bmjdrc-2021-002301 -
Expert Opinion on Pharmacotherapy Apr 2021: In the past, controlling the hormone-excess-state was the main determinant of survival in Functional-Neuroendocrine-Neoplasm-syndromes (F-NENs). This was difficult...
: In the past, controlling the hormone-excess-state was the main determinant of survival in Functional-Neuroendocrine-Neoplasm-syndromes (F-NENs). This was difficult because the pharmacological-armamentarium available was limited. Recently, new therapeutic strategies have increased but it also generated controversies/uncertainties.: The authors briefly review: established/proposed F-NENs; the rationale for treatments; the recommended initial-pharmacotherapeutic-approach to controlling F-NENs hormone-excess-state; the secondary-approaches if the initial approach fails or resistance develops; and the approach to deal with the malignant nature of the NEN. Also discussed are controversies/uncertainties related to new treatments.: Unfortunately, except for patients with insulinomas (>90-95%), gastrinomas (<20-40%), a minority with the other F-panNENs and 0-<1% with Carcinoid-syndrome is curative-surgery possible. Except for insulinomas, gastrinomas, and ACTHomas, long-acting somatostatin-analogs are the initial-pharmacological-treatments for hormone-excess-state. For insulinomas prior to surgery/malignancy, diazoxide is the initial drug-treatment; for gastrinomas, oral PPIs; and for ACTHomas, steroidogenesis inhibitors. There are now several secondary pharmacotherapeutic treatments. Surgery and liver-directed therapies also have a role in selected patients. Particularly promising is the recent results with PRRT for the hormone-excess-state, independent of its anti-growth effect. The sequence to use various agents and the approach to syndrome diagnosis while taking various agents remains unclear/controversial in many cases.
Topics: Humans; Neuroendocrine Tumors; Pancreatic Neoplasms; Somatostatin
PubMed: 33131345
DOI: 10.1080/14656566.2020.1845651 -
Diabetes & Metabolism Journal Sep 2021The year 2021 marks the 100th anniversary of the discovery of insulin, which has greatly changed the lives of people with diabetes and become a cornerstone of advances... (Review)
Review
The year 2021 marks the 100th anniversary of the discovery of insulin, which has greatly changed the lives of people with diabetes and become a cornerstone of advances in medical science. A rapid bench-to-bedside application of the lifesaving pancreatic extract and its immediate commercialization was the result of a promising idea, positive drive, perseverance, and collaboration of Banting and colleagues. As one of the very few proteins isolated in a pure form at that time, insulin also played a key role in the development of important methodologies and in the beginning of various fields of modern science. Since its discovery, insulin has evolved continuously to optimize the care of people with diabetes. Since the 1980s, recombinant DNA technology has been employed to engineer insulin analogs by modifying their amino acid sequence, which has resulted in the production of insulins with various profiles that are currently used. However, unmet needs in insulin treatment still exist, and several forms of future insulins are under development. In this review, we discuss the past, present, and future of insulin, including a history of ceaseless innovations and collective intelligence. We believe that this story will be a solid foundation and an unerring guide for the future.
Topics: Amino Acid Sequence; Diabetes Mellitus; Humans; Insulin; Insulin, Regular, Human; Insulins
PubMed: 34610718
DOI: 10.4093/dmj.2021.0163 -
Nature Reviews. Endocrinology Jun 2023Insulin and glucagon exert opposing effects on glucose metabolism and, consequently, pancreatic islet β-cells and α-cells are considered functional antagonists. The... (Review)
Review
Insulin and glucagon exert opposing effects on glucose metabolism and, consequently, pancreatic islet β-cells and α-cells are considered functional antagonists. The intra-islet hypothesis has previously dominated the understanding of glucagon secretion, stating that insulin acts to inhibit the release of glucagon. By contrast, glucagon is a potent stimulator of insulin secretion and has been used to test β-cell function. Over the past decade, α-cells have received increasing attention due to their ability to stimulate insulin secretion from neighbouring β-cells, and α-cell-β-cell crosstalk has proven central for glucose homeostasis in vivo. Glucagon is not only the counter-regulatory hormone to insulin in glucose metabolism but also glucagon secretion is more susceptible to changes in the plasma concentration of certain amino acids than to changes in plasma concentrations of glucose. Thus, the actions of glucagon also include a central role in amino acid turnover and hepatic fat oxidation. This Review provides insights into glucagon secretion, with a focus on the local paracrine actions on glucagon and the importance of α-cell-β-cell crosstalk. We focus on dysregulated glucagon secretion in obesity, non-alcoholic fatty liver disease and type 2 diabetes mellitus. Lastly, the future potential of targeting hyperglucagonaemia and applying dual and triple receptor agonists with glucagon receptor-activating properties in combination with incretin hormone receptor agonism is discussed.
Topics: Humans; Diabetes Mellitus, Type 2; Glucagon; Glucagon-Secreting Cells; Glucose; Insulin; Metabolic Diseases
PubMed: 36932176
DOI: 10.1038/s41574-023-00817-4 -
Radiologie (Heidelberg, Germany) Dec 2023
Topics: Humans; Pancreas; Pancreatic Neoplasms; Pancreatic Hormones
PubMed: 38038741
DOI: 10.1007/s00117-023-01232-6 -
Annals of Medicine Dec 2021Many patients with type 2 diabetes will ultimately require the inclusion of basal insulin in their treatment regimen. Since most people with type 2 diabetes are managed... (Review)
Review
Many patients with type 2 diabetes will ultimately require the inclusion of basal insulin in their treatment regimen. Since most people with type 2 diabetes are managed in the community, it is important that primary care providers understand and correctly manage the initiation and titration of basal insulins, and help patients to self-manage insulin injections. Newer, long-acting basal insulins provide greater stability and flexibility than older preparations and improved delivery systems. Basal insulin is usually initiated at a conservative dose of 10 units/day or 0.1-0.2 units/kg/day, then titrated thereafter over several weeks or months, based on patients' self-measured fasting plasma glucose, to achieve an individualized target (usually 80-130 mg/dL). Through a shared decision-making process, confirmation of appropriate goals and titration methods should be established, including provisions for events that might alter scheduled titration (e.g. travel, dietary change, illness, hospitalization, etc.). Although switching between basal insulins is usually easily accomplished, pharmacokinetic and pharmacodynamic differences between formulations require clinicians to provide explicit guidance to patients. Basal insulin is effective long-term, but overbasalization (continuing to escalate dose without a meaningful reduction in fasting plasma glucose) should be avoided.Key messagesPrimary care providers often initiate basal insulin for people with type 2 diabetes.Basal insulin is recommended to be initiated at 10 units/day or 0.1-0.2 units/kg/day, and doses must be titrated to agreed fasting plasma glucose goals, usually 80-130 mg/dL. A simple rule is to gradually increase the initial dose by 1 unit per day (NPH, insulin detemir, and glargine 100 units/mL) or 2-4 units once or twice per week (NPH, insulin detemir, glargine 100 and 300 units/mL, and degludec) until FPG levels remain consistently within the target range. If warranted, switching between basal insulins can be done using simple regimens.The dose of basal insulin should be increased as required up to approximately 0.5-1.0 units/kg/day in some cases. Overbasalization (continuing to escalate dose without a meaningful reduction in fasting plasma glucose) is not recommended; rather re-evaluation of individual therapy, including consideration of more concentrated basal insulin preparations and/or short-acting prandial insulin as well as other glucose-lowering therapies, is suggested.
Topics: Blood Glucose; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Insulin; Insulin Detemir; Insulin Glargine; Insulin, Long-Acting; Primary Health Care
PubMed: 34165382
DOI: 10.1080/07853890.2021.1925148